The proposed project is part of a long range research effort aimed at the development of new chemotherapeutic agents and approaches. The main objective of this research is to provide new strategies for the improvement of the therapeutic effectiveness of existing anti-AIDS drugs by introducing novel structural modifications based on molecular, biochemical and pharmacologic considerations. The proposed project focuses on the design, synthesis and study of membrane permeable prodrug derivatives of nucleoside and nucleotide analogs as potential inhibitors of human immunodeficiency virus (HIV) replication. The choice and design of target structures take into account the results of preclinical studies and current clinical experience with nucleoside analogs and aim at: effective penetration into the central nervous system; prolonged duration of action; reduced cytotoxicity and systemic toxicity; and increased intracellular availability of phosphorylated derivatives minimizing the cell-to-cell variations of antiviral activity. The specific aims of the proposed research include the design, synthesis and characterization of lipophilic prodrug forms of 2', 3'-dideoxy- nucleoside analogs as potential inhibitors of HIV replication; the study of the factors influencing the hydrolytic conversion of prodrugs to their intracellularly active forms and elucidation of the mechanisms of these reactions; conformational analysis and molecular modelling of target compounds using X-ray crystallography, molecular mechanics calculations and computer graphics techniques; the study of the cellular uptake and metabolism of radioactive isotope labelled derivatives; the measurement of reverse transcriptase inhibitory activity of the 5'-triphosphate derivatives of selected analogs; and the exploration of the usefulness of differentiating neuroblastoma cells in culture as an in vitro model system for neurotoxicity. All target compounds will be made in sufficient quantities for evaluation in various test systems for anti-HIV activity and cytotoxicity. Based on the results obtained, structure-activity relationships will be established to shape future research directions. It is likely that in addition to their potential therapeutic utility, the proposed analogs may serve as useful tools in the study of biochemical processes in retrovirus infected cells.